OP0267 A GENOME-WIDE INVESTIGATION OF PERSISTENCE TO TREATMENT WITH METHOTREXATE IN SWEDISH EARLY RHEUMATOID ARTHRITIS PATIENTS
Authors: A. Öberg Sysojev, S. Saevarsdottir, L. M. Diaz-Gallo, L. Alfredsson, L. Klareskog, T. Frisell, L. Padyukov, J. Askling, H. Westerlind
Journal: Annals of the Rheumatic Diseases (2022)

Background Despite being the anchor drug for treating rheumatoid arthritis (RA), methotrexate (MTX) provides a good response only in some of the treated patients [1]. If MTX treatment outcome has a substantial genetic component, genetic variants could provide useful predictors for identification of patients likely to respond and remain on treatment. So far, studies have focused mainly on primary response, and attempts to explain the inter-patient variability through genetic variants have been inconclusive or underpowered [2,3]. Objectives We aimed to investigate whether there are genetic variants associated with persistence to treatment with MTX (at one and three years) in early RA, and to estimate any underlying heritability. Methods We conducted a genome-wide association study (GWAS) on persistence to treatment with MTX in DMARD-monotherapy. We included participants from the Epidemiological Investigation of RA (EIRA) study and the Swedish Rheumatology Quality Register’s biobank, diagnosed with early RA and treated with MTX as their first ever DMARD. Persistence to MTX was defined as remaining on treatment at one and three years, respectively, with no additional DMARDs added during that period. Estimation of SNP-based heritability was done using restricted maximum likelihood. We performed the analyses for all RA, and two disease subsets: those positive for either ACPA or rheumatoid factor, and those negative for both. Results After quality control, 3403 of an initial 3609 early RA patients of European ancestry and above five million SNPs remained for the primary analysis. Among these, 65% were persistent at one year, and 44% were persistent at three years. In secondary analysis we excluded 218 patients due to missing sero-status. Of the remaining, 72% were seropositive. No SNP reached genome-wide significance, neither for persistence at one nor at three years. The SNP-based heritability was estimated to 0.35 (95%CI 0.04-0.65) for persistence at one year and 0.09 (95%CI 0.00-0.37) for persistence at three years. Analyses stratified by sero-status provided results comparable to the main analysis with similar proportions of persistent patients and no SNP reaching genome-wide significance for any of the subgroups. Point estimates of heritability for persistence in the seropositive group at one year (h 2 = 0.08, 95%CI 0.00-0.51) was lower than for seropositive persistence at three years (h 2 = 0.19, 95%CI 0.00-0.62) while point estimates for the seronegative heritability were zero for both persistence outcomes. Conclusion Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The low heritability observed along with the lack of strong independent associations, may indicate that genetic influence from common genetic variants on persistence to MTX is minor, and of a polygenic nature. References [1]Saevarsdottir, S., et al., Predictors of response to methotrexate in early DMARD naive rheumatoid arthritis: results from the initial open-label phase of the SWEFOT trial. Ann Rheum Dis, 2011. 70 (3): p. 469-75. [2]Ling, S., J. Bluett, and A. Barton, Prediction of response to methotrexate in rheumatoid arthritis. Expert Rev Clin Immunol, 2018. 14 (5): p. 419-429. [3]Szostak, B., et al., Using pharmacogenetics to predict methotrexate response in rheumatoid arthritis patients. Expert Opin Drug Metab Toxicol, 2020. 16 (7): p. 617-626. Acknowledgements The authors would like to thank the participants of the EIRA study and the SRQ biobank as well as deCODE genetics for making this study possible. Disclosure of Interests Anton Öberg Sysojev: None declared, Saedis Saevarsdottir Employee of: Part-time employee of deCODE genetics Inc., Lina M. Diaz-Gallo: None declared, Lars Alfredsson: None declared, Lars Klareskog: None declared, - SRQ Biobank Group: None declared, Thomas Frisell: None declared, Leonid Padyukov: None declared, Johan Askling Grant/research support from: Karolinska Institutet has entered into agreements with the following companies, with JA as PI: Abbvie, BMS, Eli Lilly, Galapagos, Janssen, Pfizer, Roche, Samsung Bioepis and Sanofi., Helga Westerlind: None declared